As is known, carotenoids, inter alia, lycopene, play an important role in the chemoprevention (prophylaxis) of cancer [see, for example, J. S. Bertram, Pure & Appl. Chem. 66, 1025-1032 (1994) and the literature references mentioned therein; N. I. Krinsky, Nat. Antioxid. Health Dis. 1994, 239-261; J. S. Bertram, Oxid, Stress Aging 1995, 221-235; as well as T. Narisawa et al., Cancer Lett. 107(1), 137-142 (1996)], and their use in clinical research is well established. [A. Bendich, Pure & Appl. Chem. 66, 1017-1024 (1994) and the literature references mentioned therein]. Levy et al. have demonstrated the preventative activity of lycopene, having the formula ##STR2##
against the growth of human endometrial, breast and lung cancer cells [Nutr. Cancer, 24, 257-266 (1995)]. E. Giovannuci et al. disclose in J. Natl. Cancer Inst. 87, 1767-1776 (1995) that a diet rich in lycopene reduces the risk of prostate cancer.
The red carotenoid lycopene is present in tomatoes and among other fruits. A finding that, with respect to the activity against cancer, cooked tomatoes are substantially more active than raw could be due to the fact that after boiling the lycopene has an improved bioavailability; on the other hand, the biologically active compound could be an oxidation product or a metabolite of lycopene. In recent investigations on the carotenoid content of human blood plasma, new lycopene metabolites have been identified, namely, 2,6-cyclolycopene-1,5-diol and 5,6-dihydroxy-5,6-dihydrolycopene [F. Khachik et al., J. Cell Biochem. 1995 (Suppl. 22), 236-246 and 11th International Symposium on Carotenoids, Leiden 1996, O.P.1.3; as well as F. Khachik, Book of Abstracts, 213th ACS Nat. Meeting, San Francisco, Apr. 13-14, 1997]. The first-mentioned known metabolite, having the formula ##STR3##
shows activity in and is useful in the prevention of cancer growth in human and mouse cells.
Two syntheses of oxidative metabolites of lycopene have been reported, namely in Biosci. Biotechn. Biochem. 59, 2153-2155 (1995; Y. Lu et al.) and in the aforementioned 11th Int. Symp. on Carotenoids, Leiden 1996 (O.P.3.5; F. Khachik et al.). These are partial syntheses, each of which starts from lycopene itself. It has now been found that 2,6-cyclolycopene-1,5-diol (II) can be made by a multi-stage process, namely starting from the readily available .alpha.-terpinyl acetate. This process is the first total synthesis of an oxidatively produced metabolite of lycopene.